Predictors of the Initiation of Islet Autoimmunity and Progression to Multiple Autoantibodies and Clinical Diabetes: The TEDDY Study
Authors: Jeffrey P. Krischer, Xiang Liu, Åke Lernmark, William A. Hagopian, Marian J. Rewers, Jin-Xiong She, Jorma Toppari, Anette-G. Ziegler, Beena Akolkar, Marian Rewers, Aaron Barbour, Kimberly Bautista, Judith Baxter, Daniel Felipe-Morales, Brigitte I. Frohnert, Marisa Stahl, Patricia Gesualdo, Michelle Hoffman, Rachel Karban, Edwin Liu, Alondra Munoz, Jill Norris, Holly O’Donnell, Stesha Peacock, Hanan Shorrosh, Andrea Steck, Megan Stern, Kathleen Waugh, Jorma Toppari, Olli G. Simell, Annika Adamsson, Sanna-Mari Aaltonen, Suvi Ahonen, Mari Åkerlund, Leena Hakola, Anne Hekkala, Henna Holappa, Heikki Hyöty, Anni Ikonen, Jorma Ilonen, Sanna Jokipuu, Leena Karlsson, Jukka Kero, Jaakko J. Koskenniemi, Miia Kähönen, Mikael Knip, Minna-Liisa Koivikko, Katja Kokkonen, Merja Koskinen, Mirva Koreasalo, Kalle Kurppa, Salla Kuusela, Jarita Kytölä, Jutta Laiho, Tiina Latva-aho, Laura Leppänen, Katri Lindfors, Maria Lönnrot, Elina Mäntymäki, Markus Mattila, Maija Miettinen, Katja Multasuo, Teija Mykkänen, Tiina Niininen, Sari Niinistö, Mia Nyblom, Sami Oikarinen, Paula Ollikainen, Zhian Othmani, Sirpa Pohjola, Jenna Rautanen, Anne Riikonen, Minna Romo, Satu Simell, Päivi Tossavainen, Mari Vähä-Mäkilä, Eeva Varjonen, Riitta Veijola, Irene Viinikangas, Suvi M. Virtanen, Jin-Xiong She, Desmond Schatz, Diane Hopkins, Leigh Steed, Jennifer Bryant, Katherine Silvis, Michael Haller, Melissa Gardiner, Richard McIndoe, Ashok Sharma, StephenW. Anderson, Laura Jacobsen, John Marks, P.D. Towe, Anette G. Ziegler, Ezio Bonifacio, Cigdem Gezginci, Anja Heublein, Eva Hohoff, Sandra Hummel, Annette Knopff, Charlotte Koch, Sibylle Koletzko, Claudia Ramminger, Roswith Roth, Jennifer Schmidt, Marlon Scholz, Joanna Stock, Katharina Warncke, Lorena Wendel, Christiane Winkler, Åke Lernmark, Daniel Agardh, Carin Andrén Aronsson, Rasmus Bennet, Corrado Cilio, Susanne Dahlberg, Ulla Fält, Malin Goldman Tsubarah, Emelie Ericson-Hallström, Lina Fransson, Thomas Gard, Emina Halilovic, Gunilla Holmén, Susanne Hyberg, Berglind Jonsdottir, Naghmeh Karimi, Helena Elding Larsson, Marielle Lindström, Markus Lundgren, Marlena Maziarz, Maria Månsson Martinez, Jessica Melin, Zeliha Mestan, Caroline Nilsson, Yohanna Nordh, Kobra Rahmati, Anita Ramelius, Falastin Salami, Anette Sjöberg, Carina Törn, Ulrika Ulvenhag, Terese Wiktorsson, Åsa Wimar, William A. Hagopian, Michael Killian, Claire Cowen Crouch, Jennifer Skidmore, Luka-Sophia Bowen, Mikeil Metcalf, Arlene Meyer, Jocelyn Meyer, Denise Mulenga, Nole Powell, Jared Radtke, Shreya Roy, Davey Schmitt, Preston Tucker, Dorothy Becker, Margaret Franciscus, MaryEllen Dalmagro-EliasSmith, Ashi Daftary, Mary Beth Klein, Chrystal Yates, Jeffrey P. Krischer, Rajesh Adusumali, Sarah Austin-Gonzalez, Maryouri Avendano, Sandra Baethke, Brant Burkhardt, Martha Butterworth, Nicholas Cadigan, Joanna Clasen, Kevin Counts, Laura Gandolfo, Jennifer Garmeson, Veena Gowda, Christina Karges, Shu Liu, Xiang Liu, Kristian Lynch, Jamie Malloy, Lazarus Mramba, Cristina McCarthy, Jose Moreno, Hemang M. Parikh, Cassandra Remedios, Chris Shaffer, Susan Smith, Noah Sulman, Roy Tamura, Dena Tewey, Michael Toth, Ulla Uusitalo, Kendra Vehik, Ponni Vijayakandipan, Melissa Wroble, Jimin Yang, Kenneth Young, Michael Abbondondolo, Lori Ballard, Rasheedah Brown, David Cuthbertson, Stephen Dankyi, Christopher Eberhard, Steven Fiske, David Hadley, Kathleen Heyman, Belinda Hsiao, Francisco Perez Laras, Hye-Seung Lee, Qian Li, Colleen Maguire, Wendy McLeod, Aubrie Merrell, Steven Meulemans, Ryan Quigley, Laura Smith, Beena Akolkar, Liping Yu, Dongmei Miao, Kathleen Gillespie, Kyla Chandler, Ilana Kelland, Yassin Ben Khoud, Matthew Randell, Stephen S. Rich, Wei-Min Chen, Suna Onengut-Gumuscu, Emily Farber, Rebecca Roche Pickin, Jonathan Davis, Jordan Davis, Dan Gallo, Jessica Bonnie, Paul Campolieto, William Hagopian, Jared Radtke, Preston Tucker, Seattle WA, Sandra Ke, Niveen Mulholland, Thomas Briese, Todd Brusko, Suzanne Bennett Johnson, Eoin McKinney, Tomi Pastinen, Eric Triplett
Journal: Diabetes Care (2022)

OBJECTIVE To distinguish among predictors of seroconversion, progression to multiple autoantibodies and from multiple autoantibodies to type 1 diabetes in young children. RESEARCH DESIGN AND METHODS Genetically high-risk newborns (n = 8,502) were followed for a median of 11.2 years (interquartile range 9.3–12.6); 835 (9.8%) developed islet autoantibodies and 283 (3.3%) were diagnosed with type 1 diabetes. Predictors were examined using Cox proportional hazards models. RESULTS Predictors of seroconversion and progression differed, depending on the type of first appearing autoantibody. Male sex, Finnish residence, having a sibling with type 1 diabetes, the HLA DR4 allele, probiotic use before age 28 days, and single nucleotide polymorphism (SNP) rs689_A (INS) predicted seroconversion to IAA-first (having islet autoantibody to insulin as the first appearing autoantibody). Increased weight at 12 months and SNPs rs12708716_G (CLEC16A) and rs2292239_T (ERBB3) predicted GADA-first (autoantibody to GAD as the first appearing). For those having a father with type 1 diabetes, the SNPs rs2476601_A (PTPN22) and rs3184504_T (SH2B3) predicted both. Younger age at seroconversion predicted progression from single to multiple autoantibodies as well as progression to diabetes, except for those presenting with GADA-first. Family history of type 1 diabetes and the HLA DR4 allele predicted progression to multiple autoantibodies but not diabetes. Sex did not predict progression to multiple autoantibodies, but males progressed more slowly than females from multiple autoantibodies to diabetes. SKAP2 and MIR3681HG SNPs are newly reported to be significantly associated with progression from multiple autoantibodies to type 1 diabetes. CONCLUSIONS Predictors of IAA-first versus GADA-first autoimmunity differ from each other and from the predictors of progression to diabetes.